ICE Bioscience Posters

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Dual-payload ADCs deliver two types of payloads to enhance efficacy through synergistic effects and mitigate resistance, thereby addressing the challenge of poorly responsive cancers and rapid patient relapses. The success of dual-payload ADCs hinges on the appropriate dual-payload combination.

DDR inhibitors are increasingly being evaluated as payloads for ADCs. To identify a rationally designed dual-payload combination that overcomes tumor heterogeneity and conventional resistance of colorectal cancer (CRC), synergistic pairs of Top 1 inhibitors and a group of DDR inhibitors with different mechanisms were screened and evaluated. A combination of a Top 1 inhibitor Exatecan and a CHK inhibitor Prexasertib showed significant synergy in CRC lines and ADC-related drug-resistant cells with both 2D and 3D cytotoxicity models. Mechanistic studies of this combination were further explored with cell cycle analysis in both LS411N and NCI-N87/DS-8201 R cells, revealing that the synergy stemmed from coordinated cell cycle arrest. Critically, the dual-payload combination did not show increased toxicity in a group of healthy human cell lines and limited or additive hematotoxicity in the CD34+ HSPC proliferation and differentiation assays, indicating a promising candidate payload pair for dual-payload ADC development.